Dimethylformamide → (Rac)-tert-butyl[6-(9-cyclopropyl-6-fluoro-3,4-dioxo-2,3,4,9-tetrahydro-isothiazolo[5,4-b]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

HRID 1640960Notes

Reaction equation

HRID 1640960 reaction equation
Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]3[C:17](=[O:18])[N:16](C(OC(C)(C)C)=O)[S:15][C:8]=3[N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:27].[C:28]([O:32][C:33](=[O:54])[NH:34][CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:41]=2)[CH2:36]1)([CH3:31])([CH3:30])[CH3:29].CN(C)C=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[C:28]([O:32][C:33](=[O:54])[NH:34][CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:2]3[CH:11]=[C:10]4[C:5]([C:6](=[O:26])[C:7]5[C:17](=[O:18])[NH:16][S:15][C:8]=5[N:9]4[CH:12]4[CH2:14][CH2:13]4)=[CH:4][C:3]=3[F:27])[CH:41]=2)[CH2:36]1)([CH3:31])([CH3:29])[CH3:30]

Participants

8

Reactant 4

HCID 6228DimethylformamideHCID 516892Sodium BicarbonateHCID 58730925tert-butyl N-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamateHCID 59999538Tert-butyl 7-bromo-9-cyclopropyl-6-fluoro-3,4-dioxoisothiazolo[5,4-B]quinoline-2(3H,4H,9H)-carboxylate

Product 1

HCID 58426875(Rac)-tert-butyl[6-(9-cyclopropyl-6-fluoro-3,4-dioxo-2,3,4,9-tetrahydro-isothiazolo[5,4-b]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 887MethanolSolventHCID 6212ChloroformSolvent

Procedure

A mixture containing 7-bromo-9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4-b]quinoline-3,4-dione (8) (31.8 mg, 0.090 mmol), 30 (68.0 mg, 0.182 mmol), tetrakis(triphenylphosphine)palladium(0) (7.2 mg, 0.006 mmol), dimethylformamide (1.5 mL), and a 1 M aqueous solution of sodium bicarbonate (360 μL, 0.360 mmol) is sparged with argon gas and irradiated with microwaves (5-min irradiation at 120° C.). The resulting green, gelatinous mixture was filtered and evaporated to dryness under reduced pressure (˜6 mm Hg, 40° C.). The recovered residue (orange oil) is washed with diethyl ether (10 mL) to give a yellow solid. This material is dissolved in a mixture containing 25% methanol in chloroform (2.0 mL), precipitated via addition of diethyl ether (10 mL), and collected by filtration; this process is repeated once. The product is washed further with water (2×10 mL) and dried in vacuo to give (rac)-tert-Butyl[6-(9-cyclopropyl-6-fluoro-3,4-dioxo-2,3,4,9-tetrahydro-isothiazolo[5,4-b]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate as a yellow solid (93% purity by HPLC; the remaining material is 9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4-b]quinoline-3,4-dione). 1HNMR (CDCl3/CD3OD (12:1 v/v), 50° C.): δ 1.10 (m, 2H, c-Pr CH2), 1.21 (m, 2H, c-Pr CH2), 1.48 (s, 9H, C(CH3)3), 1.76 (m, 1H, H-3), 2.10 (m, 1H, H-3), 2.68 (m, 1H, H-1), 2.86 (m, 2H, H-4), 3.08 (m, 1H, c-Pr CH), 3.12 (m, 1H, H-1), 3.94 (m, 1H, H-2), 7.11 (m, 1H, aromatic), 7.20 (m, 2H, aromatic), 7.71 (m, 1H, aromatic), 7.92 (m, 1H, aromatic). 19F{1H} NMR (CDCl3/CD3OD (12:1 v/v), 50° C.): δ −123.8 (s). NMR spectra collected at room temperature contained broad, unresolved signals. LCMS m/z calcd for C28H28FN3O4S ([M]+) 521. Found 522 ([M+H]+).

Workup

  1. customirradiated with microwaves (5-min irradiation at 120° C.)
  2. filtrationThe resulting green, gelatinous mixture was filtered
  3. customevaporated to dryness under reduced pressure (˜6 mm Hg, 40° C.)
  4. washThe recovered residue (orange oil) is washed with diethyl ether (10 mL)
  5. customto give a yellow solid
  6. dissolutionThis material is dissolved in a mixture
  7. customprecipitated via addition of diethyl ether (10 mL)
  8. filtrationcollected by filtration
  9. washThe product is washed further with water (2×10 mL)
  10. customdried in vacuo

Sources & evidence

ORD record
ord-6471fbef1d3340e8b7922029c0813fac
Source dataset
uspto-grants-2012_02
Patent number
US08114888B2

Reaction notes

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